ES2681698T3 - Combination vaccines with lower doses of antigen and / or adjuvant - Google Patents

Combination vaccines with lower doses of antigen and / or adjuvant Download PDF

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ES2681698T3
ES2681698T3 ES12709382.1T ES12709382T ES2681698T3 ES 2681698 T3 ES2681698 T3 ES 2681698T3 ES 12709382 T ES12709382 T ES 12709382T ES 2681698 T3 ES2681698 T3 ES 2681698T3
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saccharide
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adjuvant
antigen
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Derek O'hagan
Barbara Baudner
David A.G. SKIBINSKI
Manmohan Singh
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GlaxoSmithKline Biologicals SA
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Priority to PCT/IB2012/050989 priority patent/WO2012117377A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/0016Combination vaccines based on diphtheria-tetanus-pertussis
    • A61K39/0018Combination vaccines based on acellular diphtheria-tetanus-pertussis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
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    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/06Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/02Bacterial antigens
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/12Viral antigens
    • A61K39/295Polyvalent viral antigens; Mixtures of viral and bacterial antigens
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    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/39Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505Inorganic adjuvants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55555Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/555Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511Organic adjuvants
    • A61K2039/55566Emulsions, e.g. Freund's adjuvant, MF59
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/70Multivalent vaccine
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    • C12N2730/00Reverse Transcribing DNA Viruses
    • C12N2730/00011Reverse Transcribing DNA Viruses
    • C12N2730/10011Hepadnaviridae
    • C12N2730/10111Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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    • C12N2770/32011Picornaviridae
    • C12N2770/32611Poliovirus
    • C12N2770/32634Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/46Medical treatment of waterborne diseases characterized by the agent
    • Y02A50/462The waterborne disease being caused by a virus
    • Y02A50/465The waterborne disease being caused by a virus the virus being the poliovirus, i.e. Poliomyelitis or Polio
    • Y02A50/466The waterborne disease being caused by a virus the virus being the poliovirus, i.e. Poliomyelitis or Polio the medicinal preparation containing antigens or antibodies, e.g. vaccines, antisera

Abstract

An immunogenic composition in unit dose form for administration to a patient, comprising (i) a diphtheria toxoid, a tetanus toxoid and an acellular pertussis antigen containing a pertussis toxoid, (ii) an aluminum salt adjuvant, wherein the amount of Al +++ in the unit dose is 10 μg to less than 0.2 mg, and (iii) a TLR7 agonist adsorbed to the aluminum salt adjuvant, wherein the TLR7 agonist includes at least one phosphate or phosphonate group and wherein the aluminum salt adjuvant and the TLR7 agonist form a stable adjuvant complex that retains the ability of the aluminum salt adjuvant to adsorb antigens.

Description

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The saccharide of serogroup W135 is a polymer of disaccharide units of sialic acid-galactose. Like the saccharide of serogroup C, it has variable O-acetylation, but at positions 7 and 9 of sialic acid [41]. The structure is written as: → 4) -D-Neup5Ac (7 / 9OAc) -α- (2 → 6) -D-Gal-α- (1 →.

The saccharide of serogroup Y is similar to saccharide of serogroup W135, except that the unit that repeats in the disaccharide includes glucose instead of galactose. Like serogroup W135, it has variable O-acetylation at positions 7 and 9 of sialic acid [41]. The structure of serogroup Y is written as: → 4) -D-Neup5Ac (7 / 9OAc) -α (2 → 6) -D-Glc-α- (1 →.

The saccharides used in accordance with the invention may be O-acetylated as described above (eg, with the same O-acetylation pattern as observed in natural capsular saccharides), or they may be partially or totally de-O -acetylated in one or more positions of the saccharide rings, or they may be hyper-O-acetylated in relation to the native capsular saccharides. For example, reference 42 describes the use of serogroup Y saccharides that are more than 80% de-O-acetylated.

Saccharide residues in meningococcal conjugates may comprise full-length saccharides prepared from meningococci, and / or may comprise full-length saccharide fragments, that is, saccharides may be shorter than natural capsular saccharides observed in bacteria. The saccharides can therefore be depolymerized, depolymerization occurring during or after purification of saccharides but before conjugation. Depolymerization reduces the chain length of saccharides. A method of depolymerization involves the use of hydrogen peroxide [43]. Hydrogen peroxide is added to a saccharide (e.g., to give a final H2O2 concentration of 1%), and then the mixture is incubated (e.g., at about 55 ° C) until reduction has been achieved. of desired chain length. Another method of depolymerization involves acid hydrolysis [44]. Other depolymerization methods are known in the art. The saccharides used to prepare conjugates for use according to the invention can be obtained by any of these depolymerization methods. Depolymerization can be used in order to provide an optimal chain length for immunogenicity and / or to reduce the chain length for the physical manageability of saccharides. In some embodiments, the saccharides have the following range of degrees of average polymerization (Gp): A = 10-20; C = 12-22; W135 = 15-25; Y = 15-25. In terms of molecular weight, instead of Gp, the useful intervals are, for all serogroups: <100 kDa; 5 kDa-75 kDa; 7 kDa-50 kDa; 8 kDa-35 kDa; 12 kDa-25 kDa; 15 kDa-22 kDa. In other embodiments, the average molecular weight for saccharides of each of the meningococcal serogroups A, C, W135 and Y may be more than 50 kDa, for example, ≥75 kDa, ≥100 kDa, ≥110 kDa, ≥120 kDa, ≥130 kDa, etc. [45], and even up to 1500 kDa, in particular as determined by MALLS. For example: a MenA saccharide may be in the range of 50-500 kDa, e.g. eg, 60-80 kDa; a MenC saccharide may be in the range of 100-210 kDa; a MenW135 saccharide may be in the range of 60-190 kDa, for example, 120-140 kDa; and / or a MenY saccharide may be in the range of 60-190 kDa, p. e.g., 150-160 kDa.

If a component or composition includes both Hib and meningococcal conjugates then, in some embodiments, the mass of Hib saccharide may be substantially the same as the mass of a particular meningococcal serogroup saccharide. In some embodiments, the mass of Hib saccharide will be greater than (e.g., at least 1.5x) the mass of a particular meningococcal serogroup saccharide. In some embodiments, the mass of Hib saccharide will be less than (e.g., at least 1.5x less) the mass of a particular meningococcal serogroup saccharide.

When a composition includes saccharide of more than one meningococcal serogroup, there is an average mass of saccharide per serogroup. If substantially equal masses of each serogroup are used, then the average mass will be the same as each individual mass; where equal masses are not used, then the mean will differ, p. For example, with an amount of 10: 5: 5: 5 µg for a MenACWY mixture, the average mass is 6.25 µg per serogroup. In some embodiments, the Hib saccharide mass will be substantially the same as the average meningococcal saccharide mass per serogroup. In some embodiments, the Hib saccharide mass will be greater than (e.g., at least 1.5x) the average meningococcal saccharide mass per serogroup. In some embodiments, the mass of Hib saccharide will be less than (eg, at least 1.5x) the mean mass of the meningococcal saccharide per serogroup [46].

Meningococcal Polypeptides

The serogroup B capsular saccharide of Neisseria meningitidis is not a useful vaccine immunogen and therefore, polypeptide antigens can be used instead. For example, the "universal serogroup B meningococcal vaccine" described by Novartis Vaccines in ref. 47

A composition of the invention may include an H factor binding protein (fHBP) antigen. The fHBP antigen has been characterized in detail. It is also known as protein "741" [SEQ ID 2535 and 2536 in ref. 48], "NMB1870", "GNA1870" [refs. 49-51], "P2086", "LP2086" or "ORF2086" [52-54]. It is naturally a lipoprotein and is expressed in all meningococcal serogroups. The fHBP antigen is divided into three distinct variants [55] and it is preferred to include antigens for all variants.

A composition of the invention may include a heparin-binding Neisseria antigen (NHBA) [56]. This

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antigen was included in the genome sequence published for the meningococcal strain of serogroup B MC58 [57] as the NMB2132 gene.

A composition of the invention may include a NadA antigen. The NadA antigen was included in the genome sequence published for the meningococcal strain of serogroup B MC58 [57] as the NMB1994 gene.

A composition of the invention may include an NspA antigen. The NspA antigen was included in the genome sequence published for the meningococcal strain of serogroup B MC58 [57] as the NMB0663 gene.

A composition of the invention may include an NhhA antigen. The NhhA antigen was included in the genome sequence published for the meningococcal strain of serogroup B MC58 [57] as the NMB0992 gene.

A composition of the invention may include an App antigen. The App antigen was included in the genome sequence published for the meningococcal strain MC58 of serogroup B [57] as the NMB1985 gene.

A composition of the invention may include an Omp85 antigen. Omp85 was included in the genome sequence published for the meningococcal strain of serogroup B MC58 [57] as the NMB0182 gene.

A composition of the invention may include a meningococcal outer membrane vesicle.

Pneumococcal Saccharides

Streptococcus pneumoniae causes bacterial meningitis and existing vaccines are based on capsular saccharides. Therefore, the compositions of the invention may include at least one pneumococcal capsular saccharide conjugated to a carrier protein.

The invention may include the capsular saccharide of one or more different pneumococcal serotypes. When a composition includes saccharide antigens of more than one serotype, they are preferably prepared separately, conjugated separately and then combined. Methods for purifying pneumococcal capsular saccharides are known in the art (e.g., see reference 58) and vaccines based on purified saccharides of 23 different serotypes have been known for many years. Improvements of these methods have also been described, e.g. eg, for serotype 3 as described in reference 59, or for serotypes 1, 4, 5, 6A, 6B, 7F and 19A as described in reference 60.

The pneumococcal capsular saccharide (s) (s) will typically be selected from the following serotypes: 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and / or 33F. Therefore, in total, a composition may include a capsular saccharide of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23 or more different serotypes. Compositions that include at least 6B serotype saccharide are useful.

A useful combination of serotypes is a 7-valent combination, e.g. eg, which includes capsular saccharides of each of serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. Another useful combination is a 9-valent combination, e.g. eg, which includes capsular saccharide of each of serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F. Another useful combination is a 10-valent combination, e.g. eg, which includes capsular saccharide of each of serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F. An 11-valent combination may further include saccharide from serotype 3. A 12-valent combination may be added to the 10-valent mixture: serotypes 6A and 19A; 6A and 22F; 19A and 22F; 6A and 15B; 19A and 15B; or 22F and 15B. A 13-valent combination can be added to the 11-valent mixture: serotypes 19A and 22F; 8 and 12F; 8 and 15B; 8 and 19A; 8 and 22F; 12F and 15B; 12F and 19A; 12F and 22F; 15B and 19A; 15B and 22F; 6A and 19A, etc.

Thus, a useful 13-valent combination includes capsular saccharide of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19 (or 19A), 19F and 23F, p. eg, prepared as described in references 61 to 64. One such combination includes 6B serotype saccharide at approximately 8 μg / ml and the other 12 saccharides at concentrations of approximately 4 μg / ml each. Another such combination includes 6A and 6B serotype saccharides in approximately 8 μg / ml each and the other 11 saccharides in approximately 4 μg / ml each.

Conveyor proteins suitable for conjugates include bacterial toxins, such as diphtheria or tetanus toxins, or toxoids or mutants thereof. These are commonly used in conjugate vaccines. For example, the diphtheria toxin mutant CRM197 [65] is useful. Other suitable transport proteins include synthetic peptides [66.67], heat shock proteins [68.69], pertussis proteins [70.71], cytokines [72], lymphokines [72], hormones [72], growth factors [72], artificial proteins comprising multiple human CD4 + T cell epitopes of different pathogen derived antigens [73] such as N19 [74], H. influenzae D protein [75-77], pneumolysin [78] or derivatives thereof non-toxic [79], PspA pneumococcal surface protein [80], iron absorption proteins [81], C. difficile toxin A or B [82], recombinant exoprotein A from Pseudomonas aeruginosa (rEPA) [83], etc. .

Transporter proteins particularly useful for pneumococcal conjugate vaccines are CRM197, tetanus toxoid, diphtheria toxoid and H. influenzae protein D. CRM197 is used in PREVNAR ™. A mixture 13

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You can use CRM197 as the carrier protein for each of the 13 conjugates, and CRM197 can be present in approximately 55-60 μg / ml.

When a composition includes conjugates of more than one pneumococcal serotype, the same carrier protein can be used for each separate conjugate, or different carrier proteins can be used. In both cases, however, a mixture of different conjugates will be formed by preparing each serotype conjugate separately, and then mixing them to form a mixture of separate conjugates. Reference 84 describes the potential advantages when different carrier proteins are used in multivalent pneumococcal conjugate vaccines, but the PREVNAR ™ product successfully uses the same carrier for each of the seven different serotypes.

A transporter protein can be covalently conjugated with a pneumococcal saccharide directly or by a connector. Different connectors are known. For example, the binding can be by a carbonyl, which can be formed by reacting a free hydroxyl group of a saccharide modified with CDI [85,86] followed by reaction with a protein to form a carbamate bond. Carbodiimide condensation can be used [87]. An adipic acid linker can be used, which can be formed by coupling a free -NH2 group (e.g., introduced into a saccharide by amination) with adipic acid (using, for example, activation with diimide), and then coupling a resultant intermediate saccharide-adipic acid protein [88,89]. Other connectors include β-propionamido [90], nitrophenylethylamine [91], halogenoacrylic halides [92], glycosidic bonds [93], 6-aminocaproic acid [94], N-succinimidyl-3 (2-pyridyldithio) -propionate (SPDP) ) [95], ADH adipic acid dihydrazide [96], C4 to C12 residues [97], etc.

Reduction amination conjugation can be used. The saccharide can be oxidized first with periodate to introduce an aldehyde group, which can then form a direct covalent bond with a carrier protein by reductive amination, e.g. eg, to the ε-amino group of a lysine. If the saccharide includes multiple aldehyde groups per molecule, then this binding technique can lead to a crosslinked product, where multiple aldehydes react with multiple amines of the transporter. This cross-linking conjugation technique is particularly useful for at least pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F and 23F.

A pneumococcal saccharide may comprise a full length intact saccharide prepared from pneumococcus, and / or may comprise full length saccharide fragments, that is, saccharides may be shorter than natural capsular saccharides observed in bacteria. The saccharides, therefore, can be depolymerized, depolymerization occurring during or after purification of saccharides but before conjugation. Depolymerization reduces the chain length of saccharides. Depolymerization can be used in order to provide an optimal chain length for immunogenicity and / or to reduce the chain length for the physical manageability of saccharides. When more than one pneumococcal serotype is used, then intact saccharides can be used for each serotype, fragments for each serotype or intact saccharides for some serotypes and fragments for other serotypes.

When a composition includes saccharide of any of serotypes 4, 6B, 9V, 14, 19F and 23F, these saccharides are preferably intact. On the contrary, when a composition includes saccharide of serotype 18C, this saccharide is preferably depolymerized.

A saccharide of serotype 3 can also be depolymerized. For example, a saccharide of serotype 3 can be subjected to acid hydrolysis for depolymerization [61], e.g. eg, using acetic acid. Then, the resulting fragments can be oxidized for activation (e.g., oxidation with periodate, it can be in the presence of bivalent cations, e.g., with MgCl2), conjugated with a transporter (e.g., CRM197) under reducing conditions (eg, using sodium cyanoborohydride) and then (optionally) any aldehyde that has not reacted in the saccharide can be deactivated (eg, using sodium borohydride) [61]. The conjugation can be performed in lyophilized material, e.g. eg, after co-lyophilization of the activated saccharide and the transporter.

A saccharide of serotype 1 can be de-O-acetylated at least partially, e.g. eg, it is achieved by treatment with alkaline pH buffer [62] such as using a bicarbonate / carbonate buffer. Such de-Oacetylated saccharides (partially) can be oxidized for activation (e.g., periodate oxidation), conjugated with a transporter (e.g., CRM197) under reducing conditions (e.g., using sodium cyanoborohydride) , and then (optionally) any unreacted aldehyde in the saccharide can be deactivated (eg, using sodium borohydride) [62]. The conjugation can be carried out in lyophilized material, e.g. eg, after co-lyophilization of the activated saccharide and the vehicle.

A serotype 19A saccharide can be oxidized for activation (eg oxidation with periodate), conjugated with a transporter (eg, CRM197) in DMSO under reducing conditions and then (optionally) any unreacted aldehyde in the saccharide can be deactivate (eg, using sodium borohydride) [98]. The conjugation can be carried out in lyophilized material, e.g. eg, after co-lyophilization of the activated saccharide and the transporter.

One or more pneumococcal capsular saccharide conjugates may be present in lyophilized form.

Pneumococcal conjugates can, ideally, produce anticapsular antibodies that bind to the relevant saccharide, e.g. eg, they produce a level of anti-saccharide antibody ≥ 0.20 μg / ml [99]. Antibodies can be evaluated by enzymatic immunoassay (EIA) and / or measurement of opsonophagocytic activity (OPA). The EIA method has been

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The presence of NaCl facilitates the correct measurement of the pH before the adsorption of antigens.

Compositions of the invention include from 10 µg to less than 0.2 mg of Al +++ per unit dose, e.g. e.g., <150 μg, <100 μg, <75 μg, <50 μg, <25 μg, etc.

The compositions of the invention have an Al +++ concentration of 20 µg / ml at below 0.4 mg / ml, e.g. e.g., 5 <300 μg / ml, <250 μg / ml, <200 μg / ml, <150 μg / ml, <100 μg / ml, <75 μg / ml, <50 μg / ml, etc.

When the compositions of the invention include an aluminum-based adjuvant, sedimentation of the components may occur during storage. Therefore, the composition should be stirred before administration to a patient. The stirred composition will be a cloudy white suspension.

Toll-like receptor agonists

When the compositions include an aluminum salt adjuvant, then a TLR agonist can be adsorbed to that aluminum salt, thereby improving the immunopotentiating effect of the adjuvant [102]. This can lead to a better immune response and / or allows a reduction in the amount of aluminum in the composition while maintaining an equivalent adjuvant effect.

Therefore, the compositions of the invention include an aluminum salt (preferably a hydroxide of

15 aluminum) to which a TLR7 agonist is adsorbed (more preferably a human TLR7 agonist). The agonist and salt can form a stable adjuvant complex that retains the salt's ability to adsorb antigens.

TLR agonists with adsorption properties typically include a phosphorus-containing moiety that can undergo a ligand exchange with surface groups in an aluminum salt, e.g. eg, with surface hydroxide groups. Therefore, a useful TLR agonist can include a phosphate, a phosphonate, a phosphinate, a

20 phosphonite, a phosphinite, a phosphate, etc. TLR7 agonists for use in the invention include at least one phosphate or phosphonate group [102].

Useful adsorbent TLR2 and TLR7 agonists are described in references 102 to 106. Specific adsorbent TLR7 agonists include, but are not limited to compounds 1A to 27A in Table A on pages 79-84 of the reference. 107. For example, the TLR7 agonist may be one of:

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retained in the final vaccine at ≤100 μg / ml, preferably <10 μg / ml, each. Other components of the antigen preparations, such as neomycin (e.g., neomycin sulfate, in particular of a poliovirus component), polymyxin B (e.g., polymyxin B sulfate, in particular of a poliovirus component ), etc. They may also be present in amounts of subnanograms per dose. A possible additional component of the final vaccine that originates in the antigen preparations comes from a purification of antigens smaller than the total. Small amounts of proteins and / or genomic DNA from B. pertussis, C. diphtheriae, C. tetani and S. cerevisiae may be present. To minimize the amounts of these residual components, antigen preparations are preferably treated to remove them before the antigens are used with the invention.

When a poliovirus component is used, it will generally have been cultured in Vero cells. The final vaccine preferably contains less than 10 ng / ml, preferably ≤1 ng / ml, e.g. e.g., ≤500 pg / ml or ≤50 pg / ml of Vero cell DNA, p. ex. less than 10 ng / ml of Vero cell DNA, that is ≥50 base pairs in length.

The compositions of the invention are presented for use in packages. Suitable containers include vials and disposable syringes (preferably sterile). The methods for preparing the compositions of the invention may comprise a step of conditioning the vaccine in packages for use. Suitable containers include vials and disposable syringes (preferably sterile).

When a composition of the invention is presented in a vial, it is preferably made of a glass or plastic material. The vial is preferably sterilized before the composition is added. To avoid problems with latex-sensitive patients, the vials can be sealed with a latex-free cap. The vial may include a single dose of vaccine, or it may include more than one dose (a "multidose" vial), e.g. eg, 10 doses. When using a multidose vial, each dose should be withdrawn with a sterile needle and syringe under strict aseptic conditions, being careful to avoid contamination of the vial contents. Preferred vials are made of colorless glass.

A vial can have a cap (e.g., a Luer closure) adapted so that a pre-filled syringe can be inserted into the cap, the contents of the syringe can be ejected to the vial (e.g., to reconstitute the material lyophilized in it) and the contents of the vial can be taken back to the syringe. After removing the syringe from the vial, a needle can then be attached and the composition can be administered to a patient. The lid is preferably inside a seal or cover, so that the seal or cover must be removed before the lid can be accessed.

When the composition is packaged in a syringe, the syringe will normally not have a needle attached to it, although a separate needle can be supplied with the syringe for assembly and use. Safety needles are preferred. Typical 25.4 mm (1 inch) 23 gauge, 25.4 mm (1 inch) 25 gauge and 16 mm (5/8 inch) 25 gauge needles are typical. The syringes may be provided with detached labels on which the batch number and expiration date of the content can be printed, to facilitate record keeping. The plunger in the syringe preferably has a stop to prevent the plunger from accidentally coming out during aspiration. The syringes may have a plug and / or plunger of latex rubber. Disposable syringes contain a single dose of vaccine. The syringe in general will have a cone stopper to seal the cone before the attachment of a needle, and the cone stopper is preferably made of butyl rubber. If the syringe and the needle are packaged separately, then the needle is preferably provided with a butyl rubber protection. Gray butyl rubber is preferred. Preferred syringes are those sold under the trade name "Tip-Lok" ™.

When a glass container (eg, a syringe or a vial) is used, then it is preferred to use a container made of a borosilicate glass instead of a sodium-calcium glass.

After packaging a composition in a container, the container can be enclosed in a box for distribution, e.g. e.g., inside a cardboard box, and the box will be labeled with vaccine details, e.g. eg, your trade name, a list of vaccine antigens (eg, "recombinant hepatitis B", etc.), the presentation container (eg, "Tip-Lok pre-filled disposable syringes" or "10 x 0.5 ml single dose vials"), its dose (eg, "each contains a 0.5 ml dose"), warnings (eg, "For adult use only" or " For pediatric use only ”), an expiration date, an indication, a patent number, etc. Each box can contain more than one packaged vaccine, e.g. eg, five or ten packaged vaccines (particularly for vials).

The vaccine can be packaged together (e.g., in the same box) with a leaflet that includes details of the vaccine, e.g. eg, instructions for administration, details of the antigens within the vaccine, etc. The instructions may also contain warnings, e.g. eg, having an easily available adrenaline solution in case of anaphylactic reaction after vaccination, etc.

The packaged vaccine is preferably stored between 2 ° C and 8 ° C. It should not freeze.

Vaccines can be provided in complete liquid form (i.e., when all antigen components are in aqueous solution or suspension) after manufacture, or they can be prepared in a way that the vaccine can be prepared extemporaneously at the time / point of use mixing two components with each other. Such two component embodiments include the liquid / liquid mixture and the liquid / solid mixture, e.g. eg, mixing aqueous material with lyophilized material. For example, in one embodiment, a vaccine can be prepared by mixing: (a) a first component comprising aqueous antigens and / or adjuvants; and (b) one second

18

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a low dose of each of a diphtheria toxoid, a tetanus toxoid and a pertussis toxoid.

An aluminum-free combination vaccine comprising at least one oil-in-water emulsion adjuvant, a diphtheria toxoid, a tetanus toxoid and a pertussis toxoid, for use in a method to immunize a baby against at least diphtheria, tetanus and whooping cough (convulsive cough) giving the baby no more than two doses of the combination vaccine. The vaccine may have a low dose of each of a diphtheria toxoid, a tetanus toxoid and a pertussis toxoid.

The combination vaccine includes a pertussis toxoid. This can be incorporated into the vaccine as a protein within a cellular pertussis antigen, but it is preferred to use an acellular pertussis antigen, as described in more detail before.

In the immunization programs described herein, no more than two doses of the vaccine are administered to the baby, that is, the baby receives a single dose or two doses of the vaccine, but does not receive three (or more) doses. However, the baby can receive a third (and perhaps more) dose later in life, that is, after his first birthday or after his second birthday.

One or two doses are preferably given to the baby (i) between 1 and 5 months of age, (ii) between 2 and 4 months of age, (iii) between 3 and 5 months of age, (iv) between 6 and 16 weeks of age, or (v) between 0 and 3 months of age. For example, two doses can be administered at (i) 1 and 2 months of age, (ii) 2 and 4 months of age, (iii) 3 and 4 months of age, (iv) 2 and 3 months of age, (v) 0 and 1 month old, etc.

general

The term "comprising" encompasses "that includes" as well as "consisting", p. eg, a composition "comprising" X may consist exclusively of X or may include something additional, eg. eg, X + Y.

The word "substantially" does not exclude "completely," p. eg, a composition that is "substantially free of Y" may be completely free of Y. When necessary, the word "substantially" may be omitted from the definition of the invention.

The term "approximately" in relation to a numerical value x means, p. e.g., x ± 10%.

Unless specifically indicated, a process comprising a step of mixing two or more components does not require any specific order of mixing. Therefore, the components can be mixed in any order. When there are three components, then two components can be combined, and then the combination can be combined with the third component, etc.

When an antigen is described as being "adsorbed" to an adjuvant, it is preferred that at least 50% (by weight) of that antigen is adsorbed, e.g. e.g., 50%, 60%, 70%, 80%, 90%, 95%, 98% or more. It is preferred that both the diphtheria toxoid and the tetanus toxoid are fully adsorbed, that is, none is detectable in the supernatant liquid. Total adsorption of HBsAg can be used.

The amounts of conjugates in general are given in terms of saccharide mass (i.e., the dose of the conjugate (carrier + saccharide) as a whole is greater than the indicated dose) in order to avoid variation due to the choice of the carrier .

When a composition includes an aluminum salt adjuvant, then it preferably does not also include an oil-in-water emulsion adjuvant. Conversely, when a composition includes an oil-in-water emulsion adjuvant, then it preferably does not also include an aluminum salt adjuvant.

Phosphorus-containing groups used with the invention may exist in a series of protonated and deprotonated forms depending on the pH of the surrounding environment, for example, the pH of the solvent in which they dissolve. Therefore, although a particular form can be illustrated herein, it is intended that unless otherwise mentioned, these illustrations are merely representative and not limiting to a specific protonated or deprotonated form. For example, in the case of a phosphate group, this has been illustrated as -OP (O) (OH) 2, but the definition includes protonated forms - [OP (O) (OH2) (OH)] + and - [ OP (O) (OH2) 2] 2+ that may exist under acidic conditions and deprotonated forms - [OP (O) (OH) (O)] - and [OP (O) (O) 2] 2-which may exist in basic conditions. The invention encompasses all such forms.

TLR agonists may exist as pharmaceutically acceptable salts. Therefore, the compounds may be used in the form of their pharmaceutically acceptable salts, that is, physiologically or toxicologically tolerable salt (which includes, where appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts).

In the case of the TLR agonists shown herein that may exist in tautomeric forms (ie, in keto or enol forms), the compound can be used in all tautomeric forms.

When a compound is administered to the body as part of a composition, then that compound can

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Without adjuvant
Al hydroxide MF59 PLG Al-t lnfanrix-6

3-valent vaccines

TD
750 21626 15693 9430 23395 -

TT
13120 17868 22458 15917 23131 -

Pertactin
639 7209 10258 3946 12857 -

TP
2501 8270 7212 3679 9938 -

HAF
3982 12057 14098 14139 23008 -

6-valent vaccines

TD
1751 18914 13982 7658 23102 21581

TT
12729 16756 22229 13744 23267 15998

Pertactin
333 6299 9363 2912 5153 10809

PT
3069 3384 4823 3906 6484 6052

HAF
4558 7206 16201 15206 19383 11051

Hib
177 813 1266 654 2153 1269

HBsAg
1058 1598 2288 1053 4501 1113

Therefore, for all these antigens, the inclusion of an adjuvant increased IgG antibody titers. The best titles were seen using Al-T. The next best were with MF59, which gave better results than aluminum hydroxide alone. Titres obtained using Al-T were better for all antigens than

5 observed with Infanrix Hexa, except for pertactin.

In addition, the data shows that the good results achieved with the 3-valent vaccine are maintained even after adding PVI, Hib and HBsAg.

IgG responses were also investigated by subclass. For most of the antigens in 6valent vaccines, adjuvants had little effect on IgG1 titers, but increased IgG2a and IgG2b titers.

10 The best titers of IgG2a and IgG2b were obtained with Al-T and then with MF59.

The higher titers observed with Al-T compared with aluminum hydroxide alone, or with the mixture of aluminum salts observed in Infanrix Hexa, means that the total amount of aluminum per dose can be reduced while maintaining the potentiation of the response immune

Antigen dose reduction

The experiments were designed to investigate whether improved adjuvants could be used to reduce the amount of antigen per dose. Dilutions were made 10 times, 50 times and 100 times (with respect to the human dose, that is, to administer 1 μg, 0.2 μg or 0.1 μg of HBsAg to each mouse per 100 μl dose) of the combinations of 6-valent antigens while maintaining adjuvant concentrations.

Osmolarity and pH were measured (and, if necessary, adjusted) after dilution. For all the

20 6-valent compositions, the pH was between 6.1 and 7.0 and the osmolarity was between 275-320 mOsm / kg. A buffer control had a pH of 7.3 and 285 mOsm / kg.

Mice were immunized in the same manner as described above. Total titers of serum IgG after 2 immunizations were as follows:

Without adjuvant
Al hydroxide MF59 Al-t

1/10
1/50 1/100  1/10 1/50 1/100  1/10 1/50 1/100  1/10 1/50 1/100

TD
459 2043 137 18357 13106 7541 17431 6003 8736 21913 16807 13724

TT
7602 7929 1700 17595 9664 5531 22791 12062 13015 23570 12237 13183

24

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Claims (1)

  1. image 1
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US20180256695A1 (en) 2018-09-13

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